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Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis

Nava Almog^*, Vanessa Henke^*, Ludmila Flores, Lynn Hlatky, Andrew L. Kung, Renee D. Wright, Raanan Berger, Lloyd Hutchinson^*, George N. Naumov^*, Elise Bender^*, Lars A. Akslen^*, Eike-Gert Achilles^|| and Judah Folkman^*,1

^* Vascular Biology Program and Department of Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA;

Department of Radiation Oncology,

Department of Pediatric Oncology,

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; and

^|| Clinic for Hepatobiliary Surgery and Visceral Transplantation, University Hospital Hamburg, Germany

¹Correspondence: Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. E-mail: judah.folkman{at}childrens.harvard.edu

SPECIFIC AIMS

The aims of the study are: 1) to characterize an experimental model that recapitulates the clinical dormancy of nonangiogenic human tumors in mice; and 2) to study the physiological, cellular, and molecular mechanisms that underlie tumor dormancy that result from blocked angiogenesis.

PRINCIPAL FINDINGS

1. We show that while angiogenic liposarcomas expand rapidly after injection, dormant liposarcomas remain microscopic (Fig. 1 ) up to one-third of the normal SCID mouse life span, although they contain a significant percentage of proliferating tumor cells
At a predictable time, these tumors complete the sequential steps to achieve the angiogenic phenotype, initiate growth, and expand in size. Once dormant tumors undergo the angiogenic switch and initiate growth and expansion of mass, the tumor growth kinetics are similar to those of the angiogenic fast-growing tumors.

View larger version (44K): [in this window] [in a new window]   Figure 1. In vivo detection of orthotopically injected human tumor cells labeled with the luciferase reporter gene. A) Tumor growth of liposarcoma orthotopically injected into the retroperitoneal fat pad was monitored and quantified according to bioluminescence from labeled cells. The red line represents photon emission from mice injected with cells of the angiogenic clone 9, whereas the blue line represents that of mice injected with cells of the nonangiogenic dormant clone 4. Data are presented as mean ± SE. Eight mice were used per group (total of 16 mice per experiment) B) Representative mice that were orthotopically injected with cells from clone 9 (left) or clone 4 (right) at day 27 after injection. The gray photographic images of the mice and bioluminescence color images were superimposed. C) The presence of tumors was confirmed by histological analysis according to H&E staining (original magnification x100).

2. This tumor growth pattern is similar both in subcutaneous (s.c.) and orthotopic environments

3. The growth and expansion of the tumor mass appears to be blocked because of impaired angiogenesis
This dormant phenotype is characterized by minimal or significantly reduced intratumoral microvessel density, which increases abruptly following the angiogenic switch (Fig. 2 ) and leads to subsequent tumor growth. The scant microvessels that are observed in the microscopic dormant liposarcomas consist mainly of short clusters of endothelial cells that lack lumens.

View larger version (69K): [in this window] [in a new window]   Figure 2. Vasculature in tumors generated from clone 4. A) Histological analysis of tumor vasculature was performed by immunostaining for CD31 and VEGF receptor. Top) CD31 staining (original magnification x40). Bottom) immunohistochemistry of VEGFR (original magnification x200). B) Quantification of CD31-positive area from tumors described in A. n = 5 for number of tumors collected at each time point. Compared to tumors collected at day 14 postinjection, there is a statistically significant decrease in microvessel density (MVD) compared to tumors collected at day 60 (P=0.00199). There is statistically significant (P<0.01) increase in MVD in tumors collected after the angiogenic switch (day 138 on average).

4. Both tumor types cultured in vitro contain fully transformed cells, but only cells from the dormant human liposarcoma secrete relatively high levels of the angiogenesis inhibitors thrombospondin-1 and TIMP-1

5. This paper establishes the utility of using bioluminescence imaging to noninvasively monitor microscopic tumors over prolonged periods of time and to follow the kinetics of tumor dormancy and growth

CONCLUSIONS AND SIGNIFICANCE

The dormant human tumor, which contains fully transformed, proliferating neoplastic cells, is rendered harmless to the host by virtue of impaired angiogenesis (Fig. 3 ). This strengthens the concept that microscopic nonangiogenic dormant tumors may be a potential target for nontoxic antiangiogenic prophylactic cancer therapy. The ability to detect and treat cancer while it is still microscopic in size and years before it is symptomatic, would potentially revolutionize the management of cancer patients. Therefore, this work provides a scientific rational for the treatment of cancer with nontoxic angiogenesis inhibitors guided by biomarkers, years before the tumor can be anatomically located and before it is symptomatic.

View larger version (32K): [in this window] [in a new window]   Figure 3. Schematic diagram.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-3946fje

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This Article Abstract Full Text Free Full Text (PDF) Free All Versions of this Article: fj.05-3946fjev1 20/7/947    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Almog, N. Articles by Folkman, J. Search for Related Content PubMed PubMed Citation Articles by Almog, N. Articles by Folkman, J.